bims-mesote 2023-09-24 papers

Issue of 2023–09–24
five papers selected by
Laura Mannarino, Humanitas Research

Clin Pract. 2023 Sep 13. 13(5): 1111-1122

Pleural Fluid-to-Blood BNP Ratio May Contribute to Prognosis in Malignant Pleural Mesothelioma.

Vasiliki Tsolaki, George E Zakynthinos, Sotirios Zarogiannis, Paris Zygoulis, Ioannis Kalomenidis, Rajesh Jagirdar, Ioannis Triantafyllou, Konstantinos I Gourgoulianis, Demosthenes Makris, Epaminondas Zakynthinos.

BACKGROUND: Brain natriuretic peptide (BNP) seems to be produced from malignant mesothelial cells other than cardiomyocytes. We aimed to evaluate whether an increased pleural fluid-to-blood BNP ratio in patients with malignant pleural mesothelioma (MPM) could facilitate prognosis beyond diagnosis.
MATERIALS AND METHODS: Patients with MPM were included (observational study). One- and two-year survival and factors affecting it were tested. To evaluate the prognostic significance of the natriuretic peptide precursor B (NPPB) gene expression in MPM, we constructed a survival curve from data derived from The Cancer Genome Atlas.
RESULTS: Nineteen consecutive patients with MPM were included (age: 67 (61, 80), male 78.9%). One- and two-year survival were 52.6% and 31.6%, respectively. Age, performance status, and the other variables tested did not differ between survivors and non-survivors. Non-survivors presented higher pleural fluid BNP in two years (699 (210, 5000) vs. 379.5 (5, 567), p = 0.036) and BNP ratios than survivors (1-year: 28.75 (4.05, 150.24) vs. 3.49 (0.3, 26) p = 0.001, 2-years: 22.8 (2.42, 150.24) vs. 3.49 (0.3, 7.76), p = 0.001). One- and two-year survival rates in patients with BNP ratios above/equal to the median value (8.82) were 20% and 0%, and 88.9% and 66.7%, respectively, in patients with BNP ratios below 8.82 (p = 0.006 and p = 0.002, respectively). MPM patients with low NPPB expression presented significantly higher survival rates compared to patients with higher expressions (p = 0.032).
CONCLUSION: A high pleural fluid/blood BNP ratio, an easily performed in everyday practice, costless biomarker seems to predict poorer survival better than the commonly reported prognostic factors in MPM.

Keywords: brain natriuretic peptide; malignant pleural mesothelioma; prognosis; survival

DOI: https://doi.org/10.3390/clinpract13050099

Annu Rev Pathol. 2023 09 18.

Diffuse Pleural Mesothelioma: Advances in Molecular Pathogenesis, Diagnosis and Treatment.

Christopher A Febres-Aldana, Rachel Fanaroff, Michael Offin, Marjorie G Zauderer, Jennifer L Sauter, Soo-Ryum Yang, Marc Ladanyi.

Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in DPM, including risk factors, pathobiology, histologic subtyping, and therapeutic management, with an emphasis on a multidisciplinary approach to this complex disease. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pathol-042420-092719

Cureus. 2023 Aug;15(8): e43744

Brain Metastases With Malignant Peritoneal Mesothelioma: Never Reported Before.

Darshan Lal, Merissa Misiura, Waqas Adeel, Rizwan Tariq.

Malignant mesothelioma is a very rare diagnosis. Malignant mesotheliomas arise from surface linings of pleura, peritoneal cavity, or tunica vaginalis and pericardium with pleural malignant mesotheliomas being the most common. The incidence of brain metastases has been very low with malignant pleural mesotheliomas, but to date, there have not been any cases reported of brain metastasis with malignant peritoneal mesotheliomas. We present a patient diagnosed with malignant peritoneal mesothelioma and was successfully treated with immunotherapy for over two years but later presented with brain metastases. Although the patient had a surgical resection followed by brain radiation, he died three months after his diagnosis of brain metastases. Immunotherapy has revolutionized the treatment of malignant mesothelioma, and patients are living longer than before. We present this patient to increase awareness of brain metastases with malignant peritoneal mesothelioma. This case also highlights that we need to investigate different treatment options for brain metastases in patients with malignant mesothelioma as conventional treatment options like surgical resection and brain radiation are not very effective.

Keywords: brain met; cancer immunotherapy; malignant peritoneal mesothelioma; malignant pleural mesothelioma (mpm); mesothelioma; treatment; treatment choices

DOI: https://doi.org/10.7759/cureus.43744

Proc Natl Acad Sci U S A. 2023 Sep 26. 120(39): e2307999120

HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma.

Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of TNFα. Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout (Hmgb1ΔpMeso) and the conditional myelomonocytic-lineage HMGB1-knockout (Hmgb1ΔMylc) mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that Hmgb1ΔpMeso, whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of TNFα. Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings, Hmgb1ΔpMeso mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.

Keywords: HMGB1; asbestos; macrophages; mesothelioma; microenvironment

DOI: https://doi.org/10.1073/pnas.2307999120

Cancer Lett. 2023 Sep 18. pii: S0304-3835(23)00346-4. [Epub ahead of print] 216395

Targeting YB-1 via entinostat enhances cisplatin sensitivity of pleural mesothelioma in vitro and in vivo.

Karin Schelch, Dominik Emminger, Benjamin Zitta, Thomas G Johnson, Verena Kopatz, Sebastian Eder, Alexander Ries, Alessia Stefanelli, Petra Heffeter, Mir A Hoda, Konrad Hoetzenecker, Balazs Dome, Walter Berger, Glen Reid, Michael Grusch.

Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 p.m. cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.

Keywords: Cisplatin; Combination treatment; Entinostat; Pleural mesothelioma; YB-1

DOI: https://doi.org/10.1016/j.canlet.2023.216395